The selective expansion and growth advantage of malignant hematopoietic cells in CML may be related to their unresponsiveness to normal negative regulatory influences from the microenvironment. CML hematopoietic progenitors, in contrast to normal progenitors, demonstrate reduced b1 integrin mediated adhesion to stroma and fibronectin. Since signaling through b1 integrins inhibits normal hematopoietic rogenitor proliferation, the continuous proliferation of CML progenitors adhering to stroma may be related to abnormal b1 integrin mediated proliferation inhibition. We have demonstrated that interferon-a (IFN-a) treatment restores b1 integrin mediated adhesion of CML progenitors to stroma and fibronectin, both directly as well as indirectly through enhanced stromal production of macrophage inflammatory protein-1a (MIP-1a). We have further demonstrated that IFN-a also restores b1 integrin-mediated inhibition of CML progenitor proliferation. Our preliminary results suggest that abnormal b1 integrin-mediated signaling in CML progenitors may be due to abnormalities in integrin-cytoskeleton interactions, and that IFN-a restores normal signaling through b1 integrins in CML, at least in part, by restoring integrin-cytoskeletal interactions. Preliminary studies suggest that treatment with BCR-ABL ODNs or PTK inhibitors may restore normal adhesion and adhesion-mediated proliferation inhibition of CML progenitors. We now propose studies, in continuation of the above studies, which will be directed towards understanding the mechanisms and significance of abnormal integrin function in CML hematopoietic progenitors and its correction by IFN-a. In SPECIFIC AIM 1, we will examine the hypothesis that defective integrin-mediated adhesion and proliferation inhibition in CML progenitors may result from p210BCR-ABL tyrosine kinase-induced abnormalities in interactions between b1 integrins and cytoskeletal elements required for integrin-mediated signaling. We will examine potential mechanisms by which IFN-a may correct these abnormalities and restore normal integrin function. In SPECIFIC AIM 2, we will evaluate the significance of restored b1 integrin-mediated microenvironmental regulation of CML progenitor proliferation in the induction of hematological and cytogenetic remissions observed in patients treated with IFN-a. We hypothesize that the the CML p210BCR-ABL kinase induces abnormalities in interactions between integrins, the cytoskeleton and associated signaling proteins which result in abnormal integrin function in CML and that these abnormalities are reversed following IFN treatment. We hypothesize that restoration of integrin mediated signaling by IFN plays an important role in induction of hematological and cytogenetic remissions in CML patients treated with IFN. These studies will enhance our understanding of CML pathogenesis by identifying mechanisms by which BCR-ABL may perturb normal negative regulation of CML progenitor proliferation. These studies will also clarify the significance of IFN-a induced restoration of integrin-mediated proliferation inhibition of CML progenitors as a mechanism by which IFN-a may restore normal hematopoiesis in CML and could lead to the development of novel therapeutic approaches.